ES2498740T3 - Imidazolidine derivatives - Google Patents

Abstract

Compounds of formula (I): wherein: A is -C (O) -, -CH2-C (O) -, -C (O) -CH2- or -CH2-CH2-, D is N or CH, E is arylene which can optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl and fluoro-lower alkyl, R1 is lower alkyl-OC (O) or R4-SO2, R2 is lower alkyl or aryl, in which aryl can be optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, fluoroalkyl lower and fluoroalkoxy, R3 is aryl or heteroaryl, in which aryl or heteroaryl they may optionally be substituted with 1 to 4 substituents selected independently from the group consisting of halogen, lower alkyl, lower alkoxy, fluoroalkyl, fluoroalkoxy, COOH, lower alkyl-SO2, lower alkyl-SO2-NH, lower alkyl-SO2- N (lower alkyl), COOH-lower alkyl, hydr lower oxyalkyl, NH2- lower alkyl, N (H, lower alkyl) -lower alkyl, N (lower alkyl) 2-lower alkyl, NO2, CN, NH2-SO2, N (H, lower alkyl) -SO2, N (alkyl lower) 2-SO2, lower alkyl-NH-SO2, and lower alkyl-N (lower alkyl) -SO2, R4 is lower alkyl, aryl, or heteroaryl, wherein aryl or heteroaryl can optionally be substituted with 1 to 4 substituents selected independently from between the group consisting of halogen, lower alkyl, lower alkoxy, fluoro-lower alkyl and fluoro-lower alkoxy, and pharmaceutically acceptable salts and esters thereof, in which the term "lower" refers to a group consisting of one to seven carbon atoms.

Description

E09761672

02-09-2014

DESCRIPTION

Imidazolidine derivatives The invention relates to novel imidazolidine derivatives of formula (I):

image 1

in which: A is -C (O) -, -CH2-C (O) -, -C (O) -CH2-or -CH2-CH2-, 10 D is NIGHT, E is arylene which can be optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl and fluoro-lower alkyl, R1 is lower alkyl-OC (O) or R4-SO2, R2

it is lower alkyl or aryl, wherein aryl may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, fluoro-lower alkyl and fluoro-lower alkoxy, R3

it is aryl or heteroaryl, wherein aryl or heteroaryl may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, fluoro-lower alkyl, fluoro-lower alkoxy, COOH, lower alkyl -SO2, lower alkyl-SO2-NH,

20 lower alkyl-SO2- (lower alkyl), COOH-lower alkyl, hydroxy-lower alkyl, NH2-lower alkyl, N (H, lower alkyl)-lower alkyl, N (lower alkyl) 2-lower alkyl, NO2, CN , NH2-SO2, N (H, lower alkyl) -SO2, lower alkyl-NH-SO2 and lower alkyl-N (lower alkyl) -SO2,

R4

it is lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, fluoro-lower alkyl and fluoro-lower alkoxy, and pharmaceutically acceptable salts and esters thereof.

Furthermore, the invention relates to a process for the preparation of the aforementioned compounds, pharmaceutical preparations containing said compounds, as well as the use of said compounds for the production of pharmaceutical preparations.

Hepatic X receptors (LXR) are elements of the nuclear hormone receptor superfamily. LXRs are activated by endogenous oxiesterols and glucose and regulate the transcription of genes that control multiple metabolic pathways. Two subtypes have been described, LXRalfa and LXRbeta (Willy PJ et al., Genes Dev. 9: 1033-45, 1995; 35 Song C. et al., Proc. Natl. Acad. Sci. USA 1994, 91: 10809- 13). LXRbeta is ubiquitously expressed, while LXRalfa is predominantly expressed in cholesterol metabolizing tissues, such as the liver, adipose tissue, intestines and macrophages. LXRs modulate a variety of physiological responses, including the regulation of cholesterol absorption, the elimination of cholesterol (synthesis of bile acids) and the transport of cholesterol from peripheral tissues through plasma lipoproteins to the liver. The LXR

40 apparently also regulate genes that participate in glucose metabolism, in the metabolism of cholesterol in the brain, in cell differentiation and apoptosis, in inflammation and in infectious diseases (Geyeregger R. et al., Cell. Mol. Life Sci. 63: 524-539, 2006).

Approximately half of patients with coronary artery disease have low concentrations of

45 high-density cholesterol-lipoprotein (HDL-C) in plasma. The atheroprotective function of HDL was first pointed out for almost 25 years and has stimulated the exploration of genetic and environmental factors that influence HDL-C levels (Miller N.E., Lipids 13: 914-9, 1978). The protective function of HDL derives from its function in a process called reverse cholesterol transport (Forrester J.S. and Shah P.K., Am. J. Cardiol. 98: 1542-49, 2006). HDL is a mediator in the elimination of cholesterol in peripheral tissue cells,

50 including foamy macrophages in atherosclerotic lesions of the arterial wall. HDL transports your cholesterol to the liver and sterol metabolizing organs for conversion into bile and elimination in stool. Studies have shown that HDL-C levels are predictive of coronary artery disease risk regardless of low-density cholesterol-lipoprotein (LDL-C) levels (Gordon T. et al., Am. J. Med. 62 : 707-14, 1977).

55

Currently, the estimated age-adjusted prevalence among Americans 20 years of age or older with HDL-C levels below 35 mg / dL is 16% (men) and 5.7% (women). A substantial increase in HDL-C is currently achieved through treatment with niacin in various formulations. However, the

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Substantial unfavorable side effects limit the therapeutic potential of this approach.

It has been observed that up to 90% of the 14 million patients diagnosed with type 2 diabetes in the United States are overweight or obese, and a high proportion of patients with type 2 diabetes have abnormal concentrations of lipoproteins. Studies have shown that the prevalence of total cholesterol> 240 mg / dl is 37% in diabetic men and 44% in women. The rates of LDL-C> 160 mg / dl are 31% and 44%, and HDL-C <35 mg / dl are 28% and 11%, in diabetic men and women, respectively. Diabetes is a disease in which the patient's ability to control blood glucose levels is reduced by a partial alteration of the response to insulin action. Type II diabetes (T2D) is also called non-insulin-dependent diabetes mellitus (NIDDM) and has been shown to affect 80-90% of all diabetic patients in developed countries. In DT2, the pancreatic islets of Langerhans continue to produce insulin. However, the target organs for insulin action, mainly muscle, liver and adipose tissues, show profound resistance to insulin stimulation. The body continues to compensate by producing high levels at a non-physiological level of insulin, which is eventually reduced in the later stages of the disease, due to the depletion and failure of the pancreatic capacity to produce insulin. Thus, DT2 is a cardiovascular metabolic syndrome associated with multiple comorbidities, including insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

The first line of treatment for dyslipidemia and diabetes generally involves a low-fat and glucose diet, physical exercise and weight loss. However, compliance can be moderate, and as the disease progresses, it is necessary to treat the various metabolic deficiencies with lipid modulating agents, such as statins and fibers for dyslipidemia, and hypoglycemic drugs, for example sulfonylureas. , metformin or insulin sensitizers of the thiazolidinedione (TZD) class of PPARγ agonists, for insulin resistance. Some recent studies provide evidence that LXR modulators could result in compounds with greater therapeutic potential and, in this way, LXR modulators could improve plasma lipid profile and raise HDL-C levels (Lund EG et al., Arterioscler. Thromb. Vasc. Biol. 23: 1169-77, 2003; Mitro N. et al., Nature 445: 219-23, 2007). LXRs are also known to control the outflow of cholesterol from the foamy macrophage of atherosclerotic lesion, and it has been shown that LXR agonists are atheroprotective (Joseph SB and Tontonoz P., Curr. Opin. Pharmacol. 3: 192 -7, 2003). Thus, LXR modulators would be more effective treatments for atherosclerotic disease that underlies the cardiovascular morbidity and mortality of stroke and heart disease. Some recent observations also suggest that there is an independent effect mediated by LXRs on insulin sensitization in addition to their role in atheroprotection (Cao G. et al., J. Biol. Chem. 2003, 278: 1131-6, 2003 ). In this way, LXR modulators can also show superior therapeutic efficacy in the elevation of HDL and atheroprotection, with additional effects on diabetes, compared to current therapies.

It has been found that the new compounds of the present invention bind and selectively activate LXR-alpha and / or LXR-beta and co-activate LXR-alpha and LXR-beta. Consequently, cholesterol absorption is reduced, HDL-cholesterol is increased and inflammatory atherosclerosis is reduced. Because LXR modulators affect the multiple faces of cholesterol dyslipidemia and homeostasis combined, the new compounds of the present invention have an increased therapeutic potential compared to compounds known in the art. Therefore, they can be used in the treatment and prophylaxis of disease that are modulated by the LXR-alpha and / or LXR-beta agonists. Such diseases include increased levels of lipids and cholesterol, in particular a low level of HDL-cholesterol, a high level of LDL-cholesterol, atherosclerotic diseases, diabetes, in particular non-insulin-dependent diabetes mellitus, the syndrome Metabolic, dyslipidemia, Alzheimer's disease, sepsis and inflammatory diseases such as colitis, pancreatitis, cholestasis / fibrosis of the liver, psoriasis and other inflammatory diseases of the skin, and diseases that present an inflammatory component, such as Alzheimer's disease or an impaired / improvable cognitive function. In addition, the new compounds of the present invention can be used for the treatment of infectious diseases such as HIV, cancer and prophylaxis of age-related and inherited forms of macular degeneration (for example Stargardt's disease).

Other compounds that bind and activate LXR-alpha and LXR-beta have been previously proposed (eg, document No. WO 03/099769). However, there is still a need for new compounds with improved properties. The present invention provides new compounds of formula (I) that bind LXR-alpha and / or LXRbeta. The compounds of the present invention unexpectedly show improved pharmacological properties compared to compounds known in the art, related to, for example, stability, selectivity, bioavailability and activity.

Unless otherwise indicated, the following definitions are provided to illustrate and define the meaning and scope of the various terms used to describe the present invention.

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Here, the term "lower" is used to refer to a group consisting of one to seven, preferably one to four carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

The term "alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical with one to twenty carbon atoms, preferably with one to sixteen carbon atoms, more preferably one to ten carbon atoms The lower alkyl groups indicated below are also preferred alkyl groups.

The term "lower alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent alkyl radical with one to seven carbon atoms, preferably with one to four carbon atoms. This expression is further exemplified with radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.

The lower alkyl groups can be optionally substituted, for example with hydroxy. Such groups are called "lower hydroalkyl." Examples of hydroxy-lower alkyl groups are, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl groups, preferably hydroxyethyl.

The term "fluoro-lower alkyl" refers to monosubstituted or multiple fluorine substituted lower alkyl groups. Examples of fluoro-lower alkyl groups are, for example, CFH2, CF2H, CF3, CF3CH2, CF3 (CH2) 2, (CF3) 2CH and CF2H-CF2.

The term "amino", alone or in combination, refers to a primary, secondary or tertiary amino group linked by the nitrogen atom, in which the secondary amino group carries an alkyl or cycloalkyl substituent and the tertiary amino group carries two similar or different alkyl or cycloalkyl substituents or the two nitrogen substituents together form a ring, such as, for example, -NH2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidine-1-yl or piperidino, etc.

The term "cycloalkyl" refers to a monovalent carbocyclic radical having 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups may optionally be substituted as indicated later in the description and in the claims.

The term "alkoxy" refers to a group of formula R'-O-, wherein R 'is an alkyl. The term "lower alkoxy" refers to the group R'-O-, wherein R 'is a lower alkyl.

The term "fluoro-lower alkoxy" refers to the group R '' - O-, wherein R '' is fluoro-lower alkyl. Examples of fluoro-lower alkoxy groups are, for example, CFH2-O, CF2H-O, CF3-O, CF3CH2-O, CF3 (CH2) 2-O, (CF3) 2CH-O and CF2HCF2-O.

The term "alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably up to 10 carbon atoms. The lower alkylene groups indicated below are also preferred alkylene groups. The term "lower alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon group having 1 to 7 carbon atoms, preferably 1 to 6 or 3 to 6 carbon atoms. Alkylene or straight chain lower alkylene groups are preferred.

The term "aryl", alone or in combination, refers to the phenyl or naphthyl group, preferably to the phenyl group, which may be optionally substituted with 1 to 5, preferably 1 to 3, substituents independently selected from the group consisting of lower alkyl , lower alkoxy, halogen, hydroxy, CN, CF3, amino, aminocarbonyl, carboxy, NO2, lower dioxo-alkylene (forming, for example, a benzodioxyl group), lower alkylsulfonyl, aminosulfonyl, lower alkylcarbonyl, lower alkylcarbonyloxy, alkylcarbonyl-NH lower, lower alkoxycarbonyl, lower fluoroalkyl, lower fluoroalkoxy, lower alkoxy-lower alkyl, cycloalkyl and phenyloxy. Unless otherwise indicated, they are preferred substituents, halogen, lower alkyl, lower fluoroalkyl, lower alkoxy and lower fluoroalkoxy. In addition, the aryl groups may preferably be substituted as indicated later in the description and in the claims.

The term "heteroaryl" refers to an aromatic monocyclic ring of 5 or 6 elements, or a bicyclic ring of 9 or 10 elements, which may comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur, such as furanyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoimidazolyl, indolyl, indolyl, indole

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benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, 3-thieno [3,2-c] pyridin-4-yl and quinolinyl. Preferred heteroaryl groups are isoxazolyl and pyridinyl. A heteroaryl group may optionally have a substitution pattern as indicated above in relation to the term "aryl". In addition, the heteroaryl groups can preferably be substituted as indicated later in the description and in the claims.

The term "arylene" refers to a divalent aryl as defined above.

The compounds of formula (I) can form pharmaceutically acceptable acid addition salts. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid, or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid , acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salts" refers to said salts. The compounds of formula

(I) they can also form salts with bases. Examples of such salts are alkaline, alkaline earth and ammonium salts, such as, for example, the salts of Na, K, Ca and trimethylammonium. The term "pharmaceutically acceptable salts" also refers to said salts.

The term "pharmaceutically acceptable esters" comprises derivatives of the compounds of formula (I), in which a carboxy group has become an ester. Examples of suitable esters are esters of: lower alkyl esters, lower hydroxyalkyl, lower alkyl lower lower alkyl, lower amino alkyl, mono- or lower dialkyl amino lower alkyl, morpholino lower alkyl, pyrrolidine lower alkyl, piperidino-lower alkyl, piperazino-lower alkyl, lower alkyl-piperazino-lower alkyl and aralkyl. Esters of: methyl, ethyl, propyl, butyl and benzyl are preferred esters. Methyl and ethyl esters are especially preferred. The term "pharmaceutically acceptable esters" further comprises compounds of formula (I) in which hydroxy groups have been converted into the corresponding esters with inorganic or organic acids, such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, which are not toxic to living organisms.

In detail, the present invention relates to compounds of formula (I), in which:

image2

TO

is -C (O) -, -CH2-C (O) -, -C (O) -CH2-or -CH2-CH2-,

D

it's N or CH,

AND

it is arylene which can be optionally substituted with 1 to 4 independently selected substituents

R1 R2

from the group consisting of halogen, lower alkyl and fluoro-lower alkyl, it is lower alkyl-O-C (O) or R4-SO2, it is lower alkyl or aryl, in which aryl can be optionally substituted with one to 4 substituents

independently selected from the group consisting of halogen, lower alkyl, alkoxy

R3

lower, fluoro-lower alkyl and fluoro-lower alkoxy, is aryl or heteroaryl, in which aryl or heteroaryl may optionally be substituted with 1 to 4 substituents

independently selected from the group consisting of halogen, lower alkyl, alkoxy

lower, fluoro-lower alkyl, fluoro-lower alkoxy, COOH, lower alkyl-SO2,

lower alkyl-SO2-NH,

I rent

lower-SO2- (lower alkyl), COOH-lower alkyl, hydroxy-lower alkyl, NH2-lower alkyl,

N (H, lower alkyl)-lower alkyl, N (lower alkyl) 2-lower alkyl, NO2,

CN, NH2-SO2, N (H, alkyl

R4

lower) -SO2, lower alkyl-NH-SO2 and lower alkyl-N (lower alkyl) -SO2, is lower alkyl, aryl or heteroaryl, in which aryl or heteroaryl can be optionally substituted with 1 to 4

substituents independently selected from the group consisting of halogen, alkyl

lower, lower alkoxy, lower fluoro-alkyl and lower fluoro-alkoxy,

and pharmaceutically acceptable salts and esters thereof.

Compounds of formula (I) are individually preferred and pharmaceutically acceptable salts thereof are individually preferred, and pharmaceutically acceptable esters thereof are individually preferred, with compounds of formula (I) being particularly preferred.

The compounds of formula (I) have one or more asymmetric C atoms and, therefore, may exist as an enantiomeric mixture, stereoisomer mixture or as optically pure compounds.

Preferred compounds according to the present invention are those in which A is -C (O) -, -CH2-CH2-or -C (O)

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CH2-. Each of the groups -C (O) -, -CH2-CH2-or -C (O) -CH2- individually represents a separate preferred embodiment.

Other preferred compounds are those in which D is N. In addition, it is preferred that D is CH. Another preferred embodiment relates to a compound as defined above, wherein E is phenylene, preferably 1,3-phenylene or 1,4-phenylene. More preferably, E is 1,3-phenylene.

In addition, it is preferred that R1 is lower alkyl-O-C (O). More preferably, R1 is (CH3) 3C-O-C (O). In addition, compounds in which R1 is R4-SO2 and R4 is as defined above are also preferred.

Another preferred embodiment of the present invention relates to compounds such as those defined above, wherein R2 is lower alkyl or phenyl, in which the phenyl may optionally be substituted with 1 to 2 substituents independently selected from lower alkyl. More preferably, R2 is isopropyl, phenyl or 2-methylphenyl.

Other preferred compounds of the present invention are those in which R 3 is phenyl or pyridinyl, in which phenyl or pyridinyl may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, COOH , lower alkyl-SO2, lower alkyl SO2-NH, COOH-lower alkyl, lower hydroxyalkyl, NH2-lower alkyl, NO2, CN, NH2-SO2 and N (H, lower alkyl) -SO2. More preferably, R3 is phenyl or pyridinyl, in which phenyl or pyridinyl can be optionally substituted with 1 to 2 substituents independently selected from the group consisting of lower alkyl-SO2, lower hydroxyalkyl, NH2-lower alkyl and NH2-SO2. Even more preferably, R3 is 3-methanesulfonylphenyl, 4-hydroxymethyl-3-methanesulfonylphenyl, 3-sulfamoylphenyl, 5-methanesulfonylpyridine-3-yl or 3-aminomethylphenyl.

Other preferred compounds of the present invention are those in which R 4 is lower alkyl, phenyl or isoxazolyl, in which the phenyl or isoxazolyl may optionally be substituted with 1 to 2 substituents independently selected from the group consisting of halogen and lower alkyl . Preferably

R4

it is lower alkyl or phenyl, in which the phenyl can be optionally substituted with halogen. More preferably, R4 is ethyl, isopropyl, phenyl or 2-fluorophenyl.

In particular, preferred compounds are the compounds of formula (I) indicated in the examples as individual compounds, as well as pharmaceutically acceptable salts and esters thereof.

Compounds of formula (I) are those selected from the group consisting of:

4 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4-carboxylic acid, 4' - (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4 -yl) -biphenyl-3-carboxylic, 1-benzenesulfonyl-4- (2 ', 5'-dimethyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (3 '-methanesulfonyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one, 3' - (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4-carboxylic acid , 3 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-carboxylic, 1-benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) - 3-phenyl-imidazolidin-2-one, N- [3 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide, N- [4' - (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide, 3- [3 '- (1-benzenesulfonyl-2-oxo-3-phenyl- imidazolidin-4-yl) -biphenyl-4-yl] -propionic acid, 3 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-2-carboxylic acid, (RS) - 1-benzenesulfonyl -3-iso-propyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1- ( Propane-2-sulfonyl) -imidazolidin-2-one, 1 - ((2-fluoro-benzenesulfonyl) -3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 3 -isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1- (5-methyl-isoxazol-4-sulfonyl) -imidazolidin-2-one, 1-benzenesulfonyl-4- (4'-hydroxymethyl- 3'-methanesulfonyl-biphenyl-3-yl) -3-phenyl-imidazolidin-2-one, 3-isopropyl-1-methanesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one , 1-ethanesulfonyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 1-benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-4 -yl) -3-phenyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 1- benzenesulfonyl-3-isopropyl-4- (3'-nitro-biphenyl-3-yl) -imidazolidin-2-one, 1-benzenesulfonyl-4- (5'-fluoro-2'-methyl-biphenyl-3-yl) -3-isopropyl-i midazolidin-2-one, 1-benzenesulfonyl-3-isopropyl-4- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -imidazolidin-2-one, 3 '- (1-benzenesulfonyl acid amide) -3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic, 1-benzenesulfonyl-4- (2'-chloro-5'-fluoro-biphenyl-3-yl) -3-isopropyl- imidazolidin-2-one, 1-benzenesulfonyl-4- (5'-chloro-2'-methyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (5'- fluoro-2'-methoxy-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one,

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3 '- (1-Benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -6-chloro-biphenyl-3-carbonitrile, 3' - (1-benzenesulfonyl-3-isopropyl-) tert-butylamide 2-Oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic, 1-benzenesulfonyl-4- (5'-ethoxy-2'-fluoro-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one , 1-benzenesulfonyl-4- (2 ', 5'-dimethyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one,

5 1-benzenesulfonyl-4- (2 ', 5'-difluoro-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 4-benzenesulfonyl-6- (3'-methanesulfonyl-biphenyl-3-yl ) -1-phenyl-piperazin-2-one, 4-benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazine, C- [3 '- (4-benzenesulfonyl-1- phenyl-piperazin-2-yl) -biphenyl-3-yl] -methylamine, trans-1-benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine,

10 trans- [3 '(1-Benzenesulfonyl-4-phenyl-piperidin-3-yl) -biphenyl-3-yl] -methylamine, trans-3- (3'-methanesulfonyl-biphenyl-) acid tert-butyl ester 3-yl) -4-phenyl-piperidin-1-carboxylic acid, cis-1-benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine, tert-butyl ester of trans acid -3- (2 ', 5'-dimethyl-biphenyl-3-yl) -4-phenyl-piperidin-1-carboxylic acid, cis-3- (2', 5'-dimethyl-biphenyl acid tert-butyl ester) -3-yl) -4-phenyl-piperidin-1-carboxylic acid,

Cis-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, tert-butyl ester of trans-3- [3- ( 5-methanesulfonyl-pyridin-3-yl) -phenyl] -4-phenyl-piperidin-1-carboxylic acid, trans-3- (3'-methyl-biphenyl-3-yl) -4- tert-butyl ester phenyl-piperidin-1-carboxylic acid, cis-5- (3'-methanesulfonyl-biphenyl-3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, tert-butyl- cis-5- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -2-oxo-4-phenyl-piperidine-1-carboxylic acid ester,

Cis-5- (2 ', 5'-dimethyl-biphenyl-3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, tert-butyl-acid ester 3 - ((3 '-, ethanesulfonyl-biphenyl-3-yl) -4-o-totyl-piperazin-1-carboxylic acid, tert-butyl ester 3- [3- (5-, ethanesulfonyl-pyridine-3- il) -phenyl] -4-o-tolyl-piperazin-1-carboxylic and 4-benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-o-tolyl-piperazine, and pharmaceutically acceptable salts and esters Acceptable of them.

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Compounds of formula (I) are particularly preferred those selected from the group consisting

of: 1-benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -3-phenyl-imidazolidin-2-one, 3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) - 1- (propane-2-sulfonyl) -imidazolidin-2-one,

30 1 - ((2-Fluoro-benzenesulfonyl) -3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one 1-ethanesulfonyl-3-isopropyl-4- (3'- Riietanosulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 1-benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 1 -benzenesulfonyl-3-isopropyl-4- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -imidazolidin-2-one, 3 'acid amide - (1-benzenesulfonyl-3-isopropyl-2- oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic acid,

4-Benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazine, trans-1-benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl -piperidine, trans- [3 '(1-benzenesulfonyl-4-phenyl-piperidin-3-yl) -biphenyl-3-yl] -methylamine, cis-5- (3'-methanesulfonyl-) tert-butyl ester biphenyl-3-yl) -2-oxo-4-phenyl-piperidin-1-carboxylic acid, 3 - ((3'-methanesulfonyl-biphenyl-3-yl) -4-o-tolyl- piperazin-1-carboxylic and

4-Benzenesulfonyl-2- (3’-methanesulfonyl-biphenyl-3-yl) -1-o-tolyl-piperazine, and pharmaceutically acceptable salts and esters thereof.

It will be appreciated that the compounds of general formula (I) in the present invention can be derivatized into functional groups to provide derivatives that are capable of becoming the parent compound again in vivo.

Also, the invention relates to a process for the preparation of compounds of formula (I) as defined above, the process comprising reacting a compound of formula (II):

image3

50 with a compound of formula R1-Cl, wherein R1, R2, R3, A, D and E are as defined above.

The reactions provided above may be carried out under conditions well known to the person skilled in the art, for example as described later in the context of Schemes 1, 2 and 3 or 55 analogously thereto.

The compounds of formula (I) can be prepared by methods known in the art or as described below, in Schemes 1 to 3. All raw materials are commercially available, E09761672

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described in the literature or can be prepared by methods well known in the art. Unless otherwise indicated, R1, R2, R3, R4, A, D and E are as indicated above.

image4

5

The compounds of formula (I) can be prepared according to the methods described in Scheme 1: aziridines 4 can be synthesized by reacting chloramine-T (2, R5 = Me) or chloramine-B (2, R5 = H) with styrene derivatives 3 in the presence of catalysts such as iodine, CuCl or trioctylmethyl ammonium chloride (Aliquat 336) in a solvent, such as acetonitrile, tert-butanol, water, ethanol, phosphate buffer, dimethylformamide or mixtures thereof, at 10 temperatures of between 0 ° C and solvent reflux. This type of reaction has been described in Tetrahedron 54: 13485, 1998, and in J. Chem. Soc., Perkin Trans. 1: 3186, 2001 (stage a). Treatment of aziridine 4 with an isocyanate 5 (commercially available or described in the literature or prepared by methods well known to those skilled in the art) in the presence of a metal halide, such as sodium iodide or magnesium bromide in a solvent , such as tetrahydrofuran or dioxane at temperatures between 0 ° C and room temperature, providing sulfonyl-imidazolidinone 6 (step b). Compounds 6 in which LG represents a leaving group, such as Cl, Br, I, OM, OT or OT, can be coupled with conveniently substituted aryl or heteroaryl metal species of formula 7, preferably boronic acids or boronic acid esters, such as, for example, boronic acid methyl esters, boronic acid ethylene glycol esters or boronic acid pinacol esters, in the presence of a suitable catalyst, preferably a palladium catalyst such as dichloro [1,1'20 bis ( diphenylphosphino) ferrocene] palladium (II) or tetracis (triphenylphosphine) palladium (0) and a base, preferably sodium carbonate, potassium fluoride, potassium carbonate or triethylamine in solvents such as dioxane, water, toluene, N, N-dimethylformamide or mixtures thereof , providing compounds of formula (I), wherein R 4 represents a phenyl or 4-methylphenyl substituent (step c). The N-arylsulfonyl bond of the N-arylsulfonyl-imidazolidinones obtained in step c can be cut under reducing conditions using magnesium in methanol under reflux (see J.

25 Heterocyclic Chem. 41: 737, 2004), providing imidazolidinones 8 (step d). The sulfonylation of compounds 8 is achieved with sulfonyl chlorides 9 in solvents such as dimethylacetamide, tetrahydrofuran, dioxane or dichloromethane in the presence of bases such as sodium hydride, N-ethyl diisopropylamine or triethylamine, optionally in the presence of DMAP at a temperature of between 0ºC and the environment (stage e).

image5

An alternative synthesis of compound (I) is illustrated in Scheme 2. Starting materials 10 are known in

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literature or can be obtained following known procedures: piperidine derivatives, for example, S. Petit,

J.P. Nallet, M. Guillard, J. Dreux, R. Chermat, M. Poncelet, C. Bulach, P. Simon, C. Fontaine et al., European Journal of Medicinal Chemistry 26:19, 1991; α-piperidinones analogously to, for example, W. Barr, J.W. Cook, J. Chem. Soc. 438, 1945, or CF Koelsch, RF Raffauf, J. Am. Chem. Soc. 66: 1857, 1944. For amines, the introduction of the residue R1 = SO2R4 is achieved by treatment with sulfonyl chlorides 9 in solvents such as dichloromethane, THF, DMF or dioxane, with bases such as N-ethyl-diisopropylamine or triethylamine, optionally in the presence of DMAP at a temperature between 0 ° C and ambient (step a). For R1 = lower alkyl-OC (O), the starting material 10 can be converted to compound 12 by treatment with the corresponding lower alkyl dicarbonate 11a in tetrahydrofuran or ether in the presence of N, N-dimethyl-aminopyridine or with chloroformates of lower alkyl 11b in the presence of a base, such as Huenigs base, N-methylmorpholine or triethylamine in dioxane or CH2Cl2. For the amides, the introduction of R1 is achieved with sulfonyl chlorides 9, lower alkyl dicarbonates 11a or lower alkyl chloroformates 11b using sodium or potassium hydride, N-ethyl diisopropylamine

or triethylamine in solvents such as dimethylacetamide, tetrahydrofuran, dioxane or dichloromethane, at temperatures between 0 ° C and reflux. Palladium catalyzed cross coupling of compound 12 with a conveniently substituted aryl or heteroaryl metal species of formula 7, preferably boronic acids or boronic acid esters, such as, for example, boronic acid methyl esters, acid ethylene glycol esters boronic acid or boronic acid pinacol esters, in the presence of a suitable catalyst, preferably a palladium catalyst such as dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) or tetracis (triphenylphosphine) palladium (0) and a base, preferably sodium carbonate, potassium fluoride, potassium carbonate or triethylamine, in solvents such as dioxane, water, toluene, 1,2-dimethoxyethane, toluene, N, N-dimethylformamide or mixtures thereof, providing compounds of formula (I ) (stage b). In the event that R1 is a protective fraction, such as BOC, the desired residue R1 can be introduced in the final stage. In this case, the cleavage of the BOC group is achieved with TFA in CH2Cl2 or with HCl in alcohols, such as ethanol or methanol. The amine intermediate is then converted to the compound (I) by treatment with sulfonyl chlorides 9, lower alkyl dicarbonates 11a or lower alkyl chloroformates 11b, as described for step a for amines, and with sulfonyl chlorides 9, lower alkyl dicarbonates 11a or lower alkyl chloroformates 11b using sodium or potassium hydride, N-ethyldiisopropylamine or triethylamine in solvents such as dimethylacetamide, tetrahydrofuran, dioxane or dichloromethane, at temperatures between 0 ° C and reflux for amides.

In the event that one of the raw materials 7, 9, 10, 11 contains one or more functional groups that are not stable or that are reactive under the appropriate conditions, protective groups may be introduced (as described in, for example, "Protective Groups in Organic Chemistry", by TW Greene and PGM Wutts, 2nd ed., 1991, Wiley NY) before introducing the R1 residue or carrying out the palladium catalyzed cross coupling, using methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

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image6

The preparation of derivatives of formula (I) in which A = CH2CH2 or CH2CO and D = N is illustrated in Scheme 3. The synthesis is initiated from bromine acetyl bromide or chloroacetyl chloride 13 and amino derivative 14, which are convert bromine / chloroacetamide in the presence of bases such as triethylamine, N, N-diisopropylethylamine or Netylmorpholine into solvents such as ether, tetrahydrofuran or dichloromethane at room temperature (step a). The second key intermediate 17 can be prepared from aldehyde 16 through cyanohydrins using trimethylsilyl cyanide and bases such as triethylamine, N, N-diisopropylethylamine or N-ethylmorpholine in solvents such as ether, tetrahydrofuran, followed by reduction with reducing agents , such as lithium aluminum hydride in THF or ether (step b). Next, the compound 15 can be converted into the amine 18 with the corresponding amino alcohol 17 in a suitable solvent, such as acetonitrile, THF, DMA or DMF at a temperature between TA and reflux in the presence of a base, such as potassium or sodium carbonate (stage c). The introduction of the residue R1 = SO2R4 is achieved by treatment with sulfonyl chlorides 9 in solvents such as dichloromethane, THF, DMF or dioxane with bases such as N-ethyl diisopropylamine or triethylamine, optionally in the presence of DMAP at a temperature between 0 ° C and the environment (stage d). For R1 = lower alkyl-OC (O), the starting material 18 can be converted to compound 19 by treatment with the corresponding lower alkyl dicarbonate 11a in tetrahydrofuran or ether in the presence of N, N-dimethyl-aminopyridine or with chloroformates of lower alkyl 11b in the presence of a base, such as Huenigs base, N-methylmorpholine or triethylamine in dioxane or CH2Cl2. If necessary, the chloroformates can be prepared by reacting the lower alkyl alcohols with Cl3CCOCl in quinoline. Cyclisation in piperazin-one 20 is achieved under Mitsunobu conditions with triphenylphosphine, diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in tetrahydrofuran at a temperature between 0 ° C and RT (step e). Palladium catalyzed cross coupling of compound 20 with a conveniently substituted aryl or heteroaryl metal species of formula 7, preferably boronic acids

or boronic acid esters, such as, for example, boronic acid methyl esters, boronic acid ethylene glycol esters or boronic acid pinacol esters, in the presence of a suitable catalyst, preferably a palladium catalyst such as dichloro [1 , 1'-bis (diphenylphosphino) ferrocene] palladium (II) or tetracis (triphenylphosphine) palladium

(0)

and a base, preferably sodium carbonate, potassium fluoride, potassium carbonate or triethylamine, in solvents such as dioxane, water, 1,2-dimethoxyethane, toluene, N, N-dimethylformamide or mixtures thereof, providing compounds of formula (I) (stage f). The reduction of compound (I, with A = -CH2-C (O) -) with borane-tetrahydrofuran complex in tetrahydrofuran at temperatures between room temperature and reflux yielded compound (I, with A = -CH2- CH2-). Alternatively, compound 20 can be reduced in piperazine 21 with borane-tetrahydrofuran complex in tetrahydrofuran at temperatures between room temperature and reflux (step g) before palladium catalyzed cross coupling in compound (I) (step f) . In the event that R1 is a protective fraction, such as BOC, the desired residue R1 can be introduced in the final stage. In

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In this case, cleavage of the BOC group is achieved with TFA in CH2Cl2 or with HCl in alcohols, such as ethanol or methanol. Next, the amine intermediate is converted to compound (I) by treatment with sulfonyl chlorides 9, lower alkyl dicarbonate 11a or lower alkyl chloroformates 11b, as described for step d.

Compounds of general formula I may contain one or more stereocenters, in the event that chiral starting materials are not used, compounds I may optionally be separated into optically pure enantiomers or diastereomers by methods well known in the art, for example by chromatography of HPLC, chromatography on a chiral HPLC column or chromatography with a chiral eluent.

The conversion of a compound of formula (I) into a pharmaceutically acceptable salt can be carried out by treating said compound with an inorganic acid, for example a hydrochloric acid, such as, for example, hydrochloric acid or hydrobromic acid, or other acids. inorganic, such as sulfuric acid, nitric acid, phosphoric acid, etc., or with an organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid . One method of forming said salt is, for example, by adding 1 / n equivalents of the acid, in which n = number of acidic protons in the acid, to a solution of the compound in a suitable solvent (eg ethanol, mixture of ethanol-water, tetrahydrofuran-water mixture) and solvent removal by evaporation or lyophilization. In the event that an acidic group is present, the corresponding salts can be prepared from the compounds of formula (I) by treatment with physiologically compatible bases. A possible method for forming said salt is, for example, by adding 1 / n equivalents of a basic salt, such as, for example, M (OH) n, where M = metal or ammonium cation and n = number of anions hydroxide, to a solution of the compound in a suitable solvent (eg ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and solvent removal by evaporation or lyophilization.

The conversion of the compounds of formula (I) into pharmaceutically acceptable esters can be carried out by, for example, treatment of a suitable carboxy group present in the molecules with a suitable alcohol with a condensation reagent, such as benzotriazol-1-yloxytris hexafluorophosphate (dimethylamino) phosphonium (BOP), N, N-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'ethylcarbodiimide hydrochloride (EDCI) or O- (1,2-dihydro-2-oxo-1 tetrafluoroborate) -pyridyl) -N, N, N, N-tetramethyl-uronium (TPTU) to produce the carboxylic ester. In addition, hydroxy groups present in the compounds of formula (I) can be reacted with suitable acids under conditions analogous to those indicated above.

To the extent that their preparation is not described in the examples, the compounds of formula (I), as well as all intermediates, can be prepared according to analogous methods or according to the methods provided above. Raw materials are commercially available or are known in the art. As indicated above, it has been found that the new compounds of the present invention bind and selectively activate LXR-alpha and LXR-beta or co-activate LXR-alpha and LXR-beta. Consequently, cholesterol absorption is reduced, HDL-cholesterol is increased and inflammatory atherosclerosis is reduced. Therefore, they can be used in the treatment and prophylaxis of diseases that are modulated by the LXR-alpha and / or LXR-beta agonists. Such diseases include increased levels of lipids and cholesterol, in particular a low level of HDL-cholesterol, a high level of LDL-cholesterol, atherosclerotic diseases, diabetes, in particular non-insulin-dependent diabetes mellitus, the syndrome metabolic, dyslipidemia, sepsis and inflammatory diseases such as colitis, pancreatitis, cholestasis / fibrosis of the liver, psoriasis and other inflammatory diseases of the skin, and diseases that have an inflammatory component, such as Alzheimer's disease or an altered / improvable cognitive function. In addition, the new compounds of the present invention can be used for the treatment of infectious diseases such as HIV, as well as cancer and prophylaxis of age-related and inherited forms of macular degeneration (for example Stargardt's disease) .

Therefore, the invention also further relates to pharmaceutical compositions comprising such a compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant.

Similarly, the invention comprises compounds such as those indicated above, for use as therapeutically active substances, especially as therapeutically active substances for the treatment and / or prophylaxis of diseases that are modulated by LXR-alpha and / or LXR agonists. -beta, in particular as therapeutically active substances for the treatment and / or prophylaxis of increased lipid levels, increased cholesterol levels, low HDL-cholesterol level, high LDL-cholesterol level, atherosclerotic diseases, diabetes, non-insulin-dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, liver cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, impaired / improvable cognitive function, HIV, cancer, f forms related to

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age of macular degeneration, hereditary forms of macular degeneration and / or Stargadt's disease.

The invention further relates to the use as therapeutically active substances, especially as therapeutically active substances for the treatment and / or prophylaxis of diseases that are modulated by LXR-alpha and / or LXR-beta agonists, in particular as therapeutically active substances. for the treatment and / or prophylaxis of increased lipid levels, increased cholesterol levels, low HDL-cholesterol level, elevated LDL cholesterol level, atherosclerotic diseases, diabetes, non-insulin-dependent diabetes mellitus , metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, liver cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, altered / improvable cognitive function, HIV, cancer, age-related forms of macular degeneration, for more inherited macular degeneration and / or Stargadt's disease. Said medicaments comprise a compound as indicated above.

The prevention and / or treatment of increased lipid levels, increased cholesterol levels, atherosclerotic diseases, dyslipidemia or diabetes is the preferred indication, in particular the prevention and / or treatment of increased lipid levels, increased cholesterol levels, atherosclerotic diseases or dyslipidemia, especially the prevention and / or treatment of atherosclerotic diseases or dyslipidemia. Diabetes, particularly non-insulin-dependent diabetes mellitus, is another preferred disease.

The following tests were carried out in order to determine the activity of the compounds of the present invention. Reference information on the tests carried out can be found in Nichols J.S. et al., "Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain", Anal Biochem. 257: 112-119, 1998.

Mammalian expression vectors were constructed to express full-length human LXR-alpha and LXR-beta. Bacterial expression vectors were constructed to produce labeled versions of the ligand binding domains (DUL) of the human LXR-alpha (aa 164 to 447) and of the human LXR-beta (aa 155 to 460). To achieve this, portions of the DUL coding sequences were amplified from the full length clones by PCR and then subcloned into the plasmid vectors. The final clones were verified by DNA sequence analysis (Willy et al., Genes Dev. 9: 1033-45, 1995; Song et al., Proc. Natl. Acad. Sci. USA 91: 10809-13, 1994) .

The induction, expression and purification of DUL proteins were carried out in E. coli strain BL21 (pLysS) cells by standard methods (ref .: Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel et al.).

Radioligand binding assay

The binding of LXR-alpha and LXR-beta receptors in buffer consisting of 50 mM HEPES, pH 7.4, 10 mM NaCl and 5 mM MgCl 2 was tested. For each reaction in 96 wells, 500 ng of LXRα-DUL proteins or 700 ng of LXR-beta-DUL were joined at 80 mg or 40 mg of SPA beads, respectively, in a final volume of 50 µl by shaking. The resulting suspension was incubated for 1 h at RT and centrifuged for 2 min at 1,300 X g. The supernatant containing unbound protein was discarded and the semi-dry pellet containing the receptor coated beads was resuspended in 50 µl of buffer. Radioligand (for example 100,000 dpm of (N- (2,2,2-trifluoroethyl) -N- [4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl) -phenyl] -benzenesulfonamide)) was added and The reaction was incubated at RT for 1 h in the presence of test compounds and then the scintillation proximity count was carried out. All binding assays were carried out in 96-well plates and the amount of bound ligand was measured in a Packard TopCount using OptiPlates (Packard) plates. Dose-response curves were measured within a concentration range of 10-10 M to 10-4 M.

Luciferase transcriptional reporter gene assays

Hamster neonate kidney cells (BHK21, ATCC # CCL10) were cultured in DMEM medium containing 10% FBS at 37 ° C in an atmosphere of 95% O2: 5% CO2. The cells were seeded in 6-well plates at a density of 10 5 cells / well and then the batch was transfected with full-length LXRα or full-length LXRβ expression plasmids plus a reporter plasmid expressing luciferase under the control of elements LXR response. Transfection with the Fugene 6 reagent (Roche Molecular Biochemicals) was carried out following the proposed protocol. Six hours after transfection the cells were harvested by trypsinization and seeded in 96-well plates at a density of 104 cells / well. After 24 hours to allow cell binding, the medium was removed and replaced with 100 ml of phenol-free medium containing the test substances or control ligands (final DMSO concentration: 0.1%). After incubation of the cells for 24 hours with substances, 50 µl of the supernatant was discarded and then 50 µl of

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luciferase constant light reagent (Roche Molecular Biochemicals) to lyse the cells and initiate the luciferase reaction. Luminescence, as a measure of luciferase activity, was detected in a Packard TopCount. Transcriptional activation in the presence of a test substance was expressed as a luminescence change factor compared to that of cells incubated in the absence of the substance. The values of

5 EC50 using the XLfit program (ID Business Solutions Ltd., United Kingdom).

The compounds according to formula (I) had an activity in at least one of the above-mentioned assays (EC50 or IC50) of 1 nM to 100 µM, preferably 1 nM to 10 µM, more preferably 1 nM to 1 µM.

For example, the following compounds showed the following IC50 values in the binding assay:

Example

LXR-alpha binding IC50 [mmoles / l] LXR-beta binding IC50 [mmoles / l]

one

11,645 2,885

2

7.97 8,045

3

10,155 5,255

4

1.68 0.28

5

4.14 5,425

6

5.72 9,025

7

0.09 0.004

8

0.335 0.0745

9

0.425 0.36

10

3.35 2.69

eleven

13.03 46.14

12

0.1467 0.0243

13

2,485 0.036

14

0.01 0.006

fifteen

2,575 0.16

16

0.475 0.029

17

52,765 2,725

18

5,005 0.106

19

0.045 0.018

twenty

0.006 0.001

twenty-one

2,915 0.155

22

4,705 1,365

2. 3

2,795 0.025

24

0.048 0.001

25

2.03 0.265

26

1,985 0.315

27

6.23 3,795

28

2,955 0.505

29

2.25 0.41

30

0.095 0.0104

31

0.815 0.165

32

0.95 0.0995

33

52,745 0.53

3. 4

0.056 0.002

35

2.62 0.425

36

0.07 0.025

37

2.54 2.09

38

0.16 0.025

39

3.03 2.75

40

44,065 19,305

41

27,445 36,775

42

2,825 0.61

43

3.98 0.755

44

53,685 5.51

Four. Five

0.24 0.021

46

8,215 0.385

47

0.185 0.22

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48

5,525 0.355

49

8.88 3,745

fifty

12,325 0.165

These results were obtained by using the test indicated above.

The compounds of formula I, as well as the pharmaceutically salts thereof, can be used as medicaments, for example in the form of pharmaceutical preparations for enteric, parenteral or topical administration. They can be administered, for example, perorally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions; rectally, for example in the form of suppositories; parenterally, for example in the form of solutions or suspensions for injection or infusion solutions, or topically, for example in the form of ointments, creams or oils. Oral administration is preferred.

The production of pharmaceutical preparations can be carried out in a manner that is familiar to any person skilled in the art by combining the indicated compounds of formula I and / or the pharmaceutically acceptable salts thereof, optionally in combination with other therapeutically substances. valuable, in a form of galenic administration with therapeutically compatible, inert, non-toxic solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, can be used as carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carrier materials for soft gelatin capsules are, for example, vegetable oils, waxes, fats, and semi-solid and liquid polyols (depending on the nature of the active ingredient, however, no carrier may be necessary in the case of capsules solid jelly). They are suitable carrier materials for the production of solutions and syrups, for example, water, polyols, sucrose, invert sugar and the like. They are suitable carrier materials for solutions for injection, for example, water, alcohols, polyols, glycerol and vegetable oils. They are suitable carrier materials for suppositories, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. They are suitable carrier materials for topical preparations, glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

As pharmaceutical adjuvants, stabilizers, preservatives, wetting and emulsifying agents, consistency enhancing agents, flavor enhancing agents, salts for modifying osmotic pressure, buffer substances, solubilizers, colorants and masking agents and usual antioxidants can be considered.

The dose of the compounds of formula I may vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration and will evidently be adjusted to the individual requirements in each particular case. For adult patients, a daily dose of between about 1 and 2,000 mg, especially between about 1 and 500 mg, is considered. Depending on the severity of the disease and the exact pharmacokinetic profile, the compound could be administered with one or more units of daily doses, for example in 1 to 3 dose units.

Pharmaceutical preparations conveniently contain about 1 to 500 mg, preferably 1 to 200 mg, of a compound of formula I.

The examples below are provided in order to illustrate the present invention in greater detail. However, they are not intended to limit its scope in any way.

Examples

Example 1

4 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4-carboxylic acid

Step 1: To a suspension under stirring of chloramine B (CAS No. [127-52-6], 1.35 g) in acetonitrile (18 ml) under argon, iodine (0.16 g) was added. 4-Bromo-styrene (2.41 g) was added and the mixture was stirred for 19 h at room temperature. Dichloromethane (240 ml) and water (120 ml) were added and the mixture was extracted with dichloromethane. The organic phase was washed with water and hypersaline solution, dried over MgSO4 and K2CO3 and filtered. The filtrate was concentrated and the product was purified using column chromatography (SiO2, cyclohexane / ethyl acetate, 95: 5 => acetate

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ethyl), providing 1-benzenesulfonyl-2- (4-bromophenyl) -aziridine (1.04 g) as a colorless oil. MS: 340.0 ([M + H] +)

Step 2: To a solution under stirring of 1-benzenesulfonyl-2- (4-bromophenyl) -aziridine (1.00 g) in tetrahydrofuran (16.5 ml) under argon was added sodium iodide (0.477 g) and phenyl isocyanate (0.539 g). The mixture was stirred for 5 days at room temperature. The mixture was diluted with ethyl acetate (50 ml) and washed with water. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, cyclohexane / ethyl acetate, 1: 0 => 0: 1), providing 1-benzenesulfonyl-4- (4-bromophenyl) -3-phenyl-imidazolidine-2one (0.974 g ) in the form of a colorless solid. MS: 458.9 ([M + H] +)

Step 3: to a solution under stirring of 1-benzenesulfonyl-4- (4-bromophenyl) -3-phenyl-imidazolidin-2-one (100 mg) and 4-carboxyphenylboronic acid (57 mg) in dioxane (0.6 ml ) and water (0.4 ml) under argon was added 2M aqueous solution of sodium carbonate (0.33 ml) and dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium and dichloromethane (9 mg) adduct. The mixture was stirred at 80 ° C for 3 h. After cooling to room temperature, the mixture was filtered. The filtrate was diluted with ethyl acetate and washed with 10% aqueous KHSO4 solution. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, dichloromethane / methanol, 1: 0 => 4: 1), to provide 4 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) - Biphenyl-4-carboxylic acid (36 mg) in the form of an off-white solid. MS: 497.1 ([M-H] -)

Example 2

4 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-carboxylic acid

Similar to Example 1, step 3, 1-benzenesulfonyl-4- (4-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 1, step 2) was reacted with 3-carboxyphenylboronic acid in the presence of dichloro adduct [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 4 '- (1benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-carboxylic acid in the form of an off-white solid. MS: 497.1 ([M-H] -)

Example 3

1-Benzenesulfonyl-4- (2 ', 5'-dimethyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one

Similar to Example 1, step 3, 1-benzenesulfonyl-4- (4-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 1, step 2) was reacted with 2,5-dimethylphenylboronic acid in the presence of adduct of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 1 benzenesulfonyl-4- (2 ', 5'-dimethylbiphenyl-4-yl) -3-phenyl-imidazolidine-2 -one in the form of a colorless solid. MS: 483.2 ([M + H] +)

Example 4

1-Benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one

Similarly to Example 1, step 3, 1-benzenesulfonyl-4- (4-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 1, step 2) was reacted with boronic (3-methylsulfonylphenyl) boronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing 1 benzenesulfonyl-4- (3 ', 5'-methanesulfonyl-biphenyl-4-yl) -3-phenyl- imidazolidin-2-one in the form of an off-white solid. MS: 533.2 ([M + H] +)

Example 5

3 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4-carboxylic acid

Stage 1: A suspension under stirring of chloramine B (CAS No. [127-52-6], 2.97 g), iodine (0.353 g) and trioctylmethyl ammonium chloride (Aliquat 336, 0.562 g) in water (40 ml) under argon 3-bromo styrene (5.09 g) was added. The mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, cyclohexane / ethyl acetate, 1: 0 => 4: 1), providing 1-benzenesulfonyl-2- (3-bromophenyl) -aziridine (3.18 g) as A pale brown oil.

Step 2: analogously to Example 1, step 2, 1-benzenesulfonyl-2- (3-bromophenyl) -aziridine was reacted with phenyl isocyanate and sodium iodide, providing 1-benzenesulfonyl-4- (3-bromophenyl) -3- phenyl-imidazolidin-2-one in the form of a colorless solid. MS: 459.0 ([M + H] +)

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Step 3: Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-phenylimidazolidin-2-one was reacted with 4-carboxyphenylboronic acid in the presence of dichloro adduct [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 3 '- (1

5 benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4-carboxylic acid in the form of an off-white solid. MS: 497.0 ([M-H] -)

Example 6

10 3 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-carboxylic acid

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 5, step 2) was reacted with 3-carboxyphenylboronic acid in the presence of dichloro adduct [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 3 '- (1

Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-carboxylic acid in the form of an off-white solid. MS: 497.2 ([M-H] -)

1-Benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -3-phenyl-imidazolidin-2-one

In analogy to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 5, step 2) was reacted with boronic (3-methylsulfonylphenyl) boronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 1 benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -3-phenyl-imidazolidine- 2-one in the form of an off-white solid. MS: 533.1 ([M + H] +)

25

Example 8

N- [3 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide

Similarly to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 5, step 2) was reacted with boronic (3-methylsulfonylaminophenyl) boronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing N- [3 '- (1benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide in the form of an off-white solid. MS: 548.2 ([M + H] +)

35

Example 9

N- [4 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (4-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 1, step 2) was reacted with boronic (3-methylsulfonylaminophenyl) boronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing N- [4 '- (1benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide in the form of a colorless solid. MS: 548.2 ([M + H] +)

Four. Five

Example 10

3- [3 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4-yl] -propionic acid

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 5, step 2) was reacted with 4- (2-carboxyethyl) benzeneboronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing 3- [3 '(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidine-) 4-yl) -biphenyl-4-yl] -propionic in the form of an off-white solid. MS: 525.1 ([M-H] -)

55

Example 11

3 '- (1-Benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-2-carboxylic acid

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 5, step 2) was reacted with 2-carboxyphenylboronic acid in the presence of adduct of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 3 '- (1benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-2- carboxylic in the form of an off-white solid. MS: 497.1

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([M-H] -)

Example 12

5 1-Benzenesulfonyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one

Step 1: analogously to Example 1, step 2, 1-benzenesulfonyl-2- (3-bromophenyl) -aziridine (Example 5, step 1) was reacted with sodium iodide and isopropyl isocyanate in tetrahydrofuran, providing 1-benzenesulfonyl-4- ( 3-bromophenyl) -3-isopropyl-imidazolidin-2-one in the form of a colorless oil.

Step 2: Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropylimidazolidine-2-one was reacted with boronic acid (3-methylsulfonylphenyl) boronic acid in the presence of dichloro [1 , 1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 1-benzenesulfonyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2-one in the form of a colorless foam. EM:

15 499.0 ([M + H] +)

3-Isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1- (propane-2-sulfonyl) -imidazolidin-2-one

Step 1: 1-Benzenesulfonyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2-one was suspended (Example 12,

20 stage 2, 1.386 g) and magnesium (0.541 g) in methanol (30 ml). The mixture was heated under reflux for 4 h and subsequently filtered. The filtrate was concentrated and the product was purified by column chromatography (SiO2, cyclohexane / ethyl acetate, 7: 3 => 0: 1), providing 1-isopropyl-5- (3'-methanesulfonyl-biphenyl-3-yl ) -imidazolidin-2one (0.293 g) in the form of a colorless solid. MS: 359.1 ([M + H] +)

Step 2: To a solution of 1-isopropyl-5- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one (40 mg) in N, N-dimethylacetamide (1 ml) under argon at 0 ° C was added sodium hydride dispersion (55% in mineral oil, 6 mg). The mixture was stirred at 0 ° C for 1.5 h. Isopropylsulfonyl chloride (19 mg) was added. The mixture was stirred for 30 min at 0 ° C and overnight at room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and concentrated. The product was purified using column chromatography.

30 (SiO2, cyclohexane / ethyl acetate, 1: 0 => 0: 1), providing 3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1 (propane-2-sulfonyl) -imidazolidine -2-one (28 mg) in the form of a colorless foam. MS: 465.3 ([M + H] +)

Example 14

1- (2-Fluoro-benzenesulfonyl) -3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2-one

Similarly to Example 13, step 2, 1-isopropyl-5- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2one (Example 13, step 1) was reacted with sodium hydride and 2-fluorobenzenesulfonyl chloride, providing 1- (2-fluorobenzenesulfonyl) -3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2-one as a colorless solid. EM:

40 517.4 ([M + H] +)

Example 15

3-Isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1- (5-methyl-isoxazol-4-sulfonyl) -imidazolidin-2-one

Analogously to Example 13, step 2, 1-isopropyl-5- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2one (Example 13, step 1) was reacted with sodium hydride and 5-methyl chloride -4-isoxazolsulfonyl, providing 3-isopropyl-4 (3'-methanesulfonyl-biphenyl-3-yl) -1- (5-methyl-isoxazol-4-sulfonyl) -imidazolidin-2-one in the form of a pale brown solid . MS: 502.4 ([M-H] -)

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Example 16

1-Benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl) -3-phenyl-imidazolidin-2-one

To a solution under stirring of 1-benzenesulfonyl-4- (3-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 5, step 2, 129 mg) and 2-methanesulfonyl-4- (4,4, 5,5-tetramethyl- [1,3,2] dioxaborollan-2-yl) -phenyl] -methanol (CAS # [918328-16-2], 80 mg) in 1,2-dimethoxyethane (2 ml) under argon cesium fluoride (87 mg) and tetracis (triphenylphosphine) palladium (0) (45 mg) were added. The mixture was stirred at 80 ° C for 18 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with hypersaline solution and concentrated. It was purified

60 the product using column chromatography (SiO2, cyclohexane / ethyl acetate, 1: 0 => 0: 1), providing 1 benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl) -3 -phenyl-imidazolidin-2-one (33 mg) in the form of a colorless solid. MS: 621.3 ([M + OAc])

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Example 17

3-Isopropyl-1-methanesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one

5 Analogously to Example 13, step 2, 1-isopropyl-5- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2one (Example 13, step 1) was reacted with sodium hydride and methanesulfonyl chloride to provide 3-Isopropyl-1methanesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one in the form of an off-white solid. MS: 454.4 ([M + NH4] +)

10 1-Etanosulfonyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one

Analogously to Example 13, step 2, 1-isopropyl-5- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2one (Example 13, step 1) was reacted with sodium hydride and ethanesulfonyl chloride to provide 1 -etanosulfonyl-3-isopropyl4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one in the form of a colorless solid. MS: 468.3 ([M + NH4] +)

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Example 19

1-Benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one

In analogy to Example 16, 1-benzenesulfonyl-4- (4-bromophenyl) -3-phenyl-imidazolidin-2-one (Example 1, step 2) was reacted with 2-methanesulfonyl-4- (4,4,5 , 5-tetramethyl- [1,3,2] dioxaborollan-2-yl) -phenyl] -methanol (CAS # [918328-16-2]) in 1,2-dimethoxyethane in the presence of cesium fluoride and tetracis (triphenylphosphine ) palladium (0), providing 1-benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one as a colorless solid. MS: 563.3 ([M + H] +)

25

Example 20

1-Benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

30 To a solution under stirring of 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1, 146 mg) and 2-methanesulfonyl-4- (4,4, 5,5-tetramethyl- [1,3,2] dioxaborollan-2-yl) -phenyl] -methanol (CAS # [918328-162], 90 mg) in 1,2-dimethoxyethane (1.5 ml) under argon Cesium fluoride (88 mg), dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane adduct (12 mg) and a 1 M aqueous solution of sodium carbonate (0.72 ml) were added. The mixture was stirred at 80 ° C for 36 h. After cooling to room temperature, water and the mixture were added

35 was extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified using column chromatography (SiO2, cyclohexane / ethyl acetate, 1: 0 => 0: 1), providing 1-benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl ) -3-Isopropyl-imidazolidin-2-one (70 mg) in the form of an off-white solid. MS: 545.9 ([M + NH4] +)

40 Example 21

1-Benzenesulfonyl-3-isopropyl-4- (3'-nitro-biphenyl-3-yl) -imidazolidin-2-one

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidine was reacted

2-one (Example 12, step 1) with (3-nitrophenyl) boronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane adduct and dioxane / water sodium carbonate, providing 1 benzenesulfonyl- 3-Isopropyl-4- (3'-nitrobiphenyl-3-yl) -imidazolidin-2-one in the form of a pale yellow oil. MS: 466.0 ([M + H] +)

50 Example 22

1-Benzenesulfonyl-4- (5'-fluoro-2'-methyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidine was reacted

2-one (Example 12, step 1) with 5-fluoro-2-methylphenylboronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] adduct palladium and dichloromethane and sodium carbonate in dioxane / water, providing 1 benzenesulfonyl -4- (5'-Fluoro-2'-methylbiphenyl-3-yl) -3-isopropyl-imidazolidin-2-one in the form of a pale yellow oil. MS: 453.1 ([M + H] +)

60 Example 23

1-Benzenesulfonyl-3-isopropyl-4- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -imidazolidin-2-one

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Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1) was reacted with 5- (methylsulfonyl) -3-pyridine-boronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing 1 benzenesulfonyl-3-isopropyl-4- [3- (5-methanesulfonyl-pyridin-3-yl ) -phenyl] -imidazolidin-2-one in the form of a yellow oil

5 pale. MS: 499.9

Example 24

3 '- (1-Benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic acid amide

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidine-2-one (Example 12, step 1) was reacted with 3-boronobenzenesulfonamide in the presence of dichloro adduct [1 , 1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 3 '- (1-benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3 acid amide -sulfonic in the form of a colorless solid. EM:

15 499.9 ([M + H] +)

Example 25

1-Benzenesulfonyl-4- (2'-chloro-5'-fluoro-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

20 Similarly to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1) was reacted with 2-chloro-5-fluorophenylboronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing 1-benzenesulfonyl-4- (2'-chloro-5'-fluoro-biphenyl-3-yl) -3- Isopropyl-imidazolidin-2-one in the form of a pale yellow oil.

25 MS: 472.9 ([M + H] +)

Example 26

1-Benzenesulfonyl-4- (5'-chloro-2'-methyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

In analogy to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1) was reacted with 5-chloro-2-methylphenylboronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing 1-benzenesulfonyl-4- (5'-chloro-2'-methylbiphenyl-3-yl) -3-isopropyl- imidazolidin-2-one in the form of a pale yellow oil.

35 MS: 469.1 ([M + H] +)

Example 27

1-Benzenesulfonyl-4- (5'-fluoro-2'-methoxy-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidine-2-one (Example 12, step 1) was reacted with 5-fluoro-2-methoxyphenylboronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing 1-benzenesulfonyl-4- (5'-fluoro-2'-methoxy-biphenyl-3-yl) -3- Isopropyl-imidazolidin-2-one in the form of an off-white solid.

45 MS: 469.2 ([M + H] +)

Example 28

3 '- (1-Benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -6-chloro-biphenyl-3-carbonitrile

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1) was reacted with boronic (2-chloro-5-cyanophenyl) boronic acid in the presence of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate adduct in dioxane / water, providing 3 '- (1benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) - 6-Chloro-biphenyl-3-carbonitrile in the form of a pale yellow oil.

55 MS: 480.0 ([M + H] +)

Example 29

3 '- (1-Benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic acid tert-Butylamide

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1) was reacted with 3-tert-butylsulfamoyl-benzeneboronic acid in the presence of adduct of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing tert

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3 '- (1-Benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic acid butylamide in the form of a whitish oil. MS: 572.8 ([M + NH4] +)

1-Benzenesulfonyl-4- (5'-ethoxy-2'-fluoro-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1) was reacted with 5-ethoxy-2-fluorophenylboronic acid in the presence of adduct of dichloro [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 1 benzenesulfonyl-4- (5'-ethoxy-2'-fluoro-biphenyl-3-yl) -3-isopropyl -imidazolidin-2-one in the form of a pale yellow oil. MS: 483.2 ([M + H] +)

Example 31

1-Benzenesulfonyl-4- (2 ', 5'-dimethyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidin-2-one (Example 12, step 1) was reacted with 2,5-dimethylphenylboronic acid in the presence of dichloro adduct [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 1-benzenesulfonyl-4- (2 ', 5'-dimethyl-biphenyl-3-yl) -3-isopropyl-imidazolidine-2 -one in the form of a pale yellow oil. MS: 449.2 ([M + H] +)

Example 32

1-Benzenesulfonyl-4- (2 ', 5'-difluoro-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one

Analogously to Example 1, step 3, 1-benzenesulfonyl-4- (3-bromophenyl) -3-isopropyl-imidazolidine-2-one (Example 12, step 1) was reacted with 2,5-difluorophenylboronic acid in the presence of dichloro adduct [1,1'bis (diphenylphosphino) ferrocene] palladium and dichloromethane and sodium carbonate in dioxane / water, providing 1 benzenesulfonyl-4- (2 ', 5'-difluoro-biphenyl-3-yl) -3-isopropyl-imidazolidine-2 -one in the form of a colorless solid. MS: 457.2 ([M + H] +)

Example 33

4-Benzenesulfonyl-6- (3'-methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazin-2-one

Step 1: To a solution under cooling of 3-bromobenzaldehyde (1.58 ml) in THF (15 ml), trimethylsilyl cyanide (1.7 ml) and N, N-diisopropylethylamine (0.23 ml) were added. The mixture was stirred at room temperature for 2 d and under reflux for 2 h. The solution was allowed to cool to room temperature and then slowly added to a suspension under cooling of lithium aluminum hydride (769 mg) in THF (10 ml). The mixture was stirred at 0 ° C for 10 min, the cooling bath was removed and the mixture was heated under reflux for 3 h. After cooling to room temperature, ethyl acetate was added slowly, followed by a mixture of Na2SO4 / silica gel / H2O. After stirring the suspension for 30 min, the mixture was filtered, the filtrate was dried (Na2SO4) and concentrated in vacuo. The residue was purified using chromatography (SiO2, CH2Cl2 / MeOH / ammonium, 90: 10: 2), to provide 2-amino-1- (3-bromophenyl) -ethanol (1.59 g) as a yellow oil.

Step 2: at 0 ° C a solution of aniline (2.45 ml) and triethylamine (0.73 ml) in methylene chloride (30 ml) was added dropwise a solution of chloroacetyl chloride (2.56 ml) in methylene chloride (10 ml). The reaction was stirred at 0 ° C for 30 min and then at room temperature for 1 hour. A 1 M aqueous solution of KHSO4 was added, the phases were separated and the inorganic was extracted with ethyl acetate (x3). The pooled organic layers were washed with water, hypersaline solution, dried (Na2SO4) and concentrated in vacuo, yielding crude 2-chloro-N-phenylacetamide, which was subjected to the next reaction without further purification.

Step 3: to a solution of crude 2-amino-1- (3-bromophenyl) -ethanol (Example 33, step 1, 1.34g) and 2-chloro-N-phenyl-acetamide (Example 33, step 2 1.0 g) in acetonitrile (15 ml) potassium carbonate (1.03 g) was added. The mixture was heated at 80 overnight. A 1M solution of KH2PO4 was added, followed by ethyl acetate. The phases were separated and the inorganic was extracted with ethyl acetate (x2). The pooled organic layers were washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, CH2Cl2 / MeOH 95: 5), followed by precipitation from a mixture of diethyl ether / n-heptane (1: 4) provided 2- [2- (3-bromophenyl) -2-hydroxy- ethylamino] -N-phenyl-acetamide (0.87 g, 42%) as a white solid, MS: 349.1 (M + H, IBr) +.

Step 4: to a suspension under cooling of 2- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -N-phenyl-acetamide (840 mg) and N, N-diisopropylethylamine (760 ml) in methylene chloride (20 ml) benzenesulfonyl chloride (0.31 ml) was added. The

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The mixture was stirred at 0 ° C for 1 hour and overnight at room temperature. A 1 M aqueous solution of KHSO4 was added, the phases were separated and the inorganic was extracted with ethyl acetate (x2). The pooled organic layers were washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, n-heptane / ethyl acetate, 1: 1), providing 2 {benzenesulfonyl- [2- (3-bromophenyl) -2-hydroxyethyl] amino} -N-phenyl-acetamide (1.17 g, 99%) in the form of a white foam, MS: 489.0 (M + H, 1Br) +.

Step 5: at 0 ° C a solution of 2- {benzenesulfonyl- [2- (3-bromophenyl) -2-hydroxy-ethyla] -amino} -N-phenylacetamide (1.15 g) and triphenylphosphine (678 mg) was added in ethyl acetate (10 ml) a solution of diethyl azodicarboxylate (0.4 ml) in ethyl acetate (5 ml) was added dropwise. After 15 min, the cooling bath was removed and the mixture was stirred at RT for 3 h. Additional amounts of triphenylphosphine (31 mg) and diethyl azodicarboxylate (0.18 ml) were added and stirring was continued for 1 h. The mixture was diluted with water and ethyl acetate, the phases were separated and the inorganic was extracted with ethyl acetate (x2). The organic layers were pooled, washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, n-heptane / ethyl acetate, 7: 3), to provide 4-benzenesulfonyl-6- (3-bromophenyl) -1-phenyl-piperazine-2one (0.99 g , 89%) in the form of a white foam, MS: 471.4 (M + H, 1Br) +.

Step 6: to a solution of 4-benzenesulfonyl-6- (3-bromophenyl) -1-phenyl-piperazin-2-one (100 mg), boronic (3-methylsulfonylphenyl) boronic acid (46.7 mg) and tetracis (triphenylphosphine) ) Palladium (0) (24.5 mg) in 1,2-dimethoxyethane (2 ml) potassium carbonate (73.3 mg) was added. The reaction mixture was stirred at 80 ° C overnight. Additional amounts of (3-methylsulfonylphenyl) boronic acid (21 mg), potassium carbonate (58.6 mg) and tetracis (triphenylphosphine) palladium (0) (24.5 mg) were added and stirring was continued at 80 ° C for 3 h . Water and ethyl acetate were added to the reaction mixture, the phases were separated and the inorganic was extracted with ethyl acetate (x2). The organic layers were pooled, washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, n-heptane / ethyl acetate, 1: 3, followed by Isolute Flash NH2, n-heptane / ethyl acetate, 1: 1), yielding 58 mg (50% ) of 4-benzenesulfonyl-6- (3'methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazin-2-one in the form of a white foam, MS: 547.3 (M + H) +.

Example 34

4-Benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazine

A solution of borane in THF (1 M, 274.4 ml) was added to a solution of 4-benzenesulfonyl-6- (3'-methanesulfonylbiphenyl-3-yl) -1-phenyl-piperazin-2-one (50 mg ) in THF (1.5 ml). The reaction mixture was heated at 85 ° C for 3 hours. An aqueous solution of KH2PO4 (1 M, 2 ml) was added slowly and the biphasic mixture was heated at 75 ° C for 15 min and then poured into a saturated sodium bicarbonate solution. Ethyl acetate was added and the phases were separated and the inorganic was extracted with ethyl acetate (x2). The organic layers were pooled, washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane / ethyl acetate 1: 1) yielded 4-benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazine (14 mg, 29%) as of a white foam, MS: 533.3 (M + H) +.

Example 35

C- [3 '- (4-Benzenesulfonyl-1-phenyl-piperazin-2-yl) -biphenyl-3-yl] -methylamine

Step 1: analogously to Example 33, step 6, starting from 4-benzenesulfonyl-6- (3-bromophenyl) -1-phenyl-piperazin-2-one and (3-cyanophenyl) boronic acid, 3 '- (4 -benzenesulfonyl-6-oxo-1-phenyl-piperazin-2-yl) -biphenyl-3-carbonitrile in the form of a white foam, MS: 494.0 ([M + H] +)

Step 2: Analogously to Example 34, starting from 3 '- (4-benzenesulfonyl-6-oxo-1-phenyl-piperazin-2-yl) -biphenyl-3carbonitrile C- [3' - (4-benzenesulfonyl-) was prepared 1-phenyl-piperazin-2-yl) -biphenyl-3-yl] -methylamine in the form of a white foam, MS: 484.4 ([M + H] +)

Example 36

trans-1-Benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine

Stage 1: to the hydrochloride salt of rac-trans-3- (m-chlorophenyl) -4-phenylpiperidine (CAS reg. No. Reg. [134823-41-9]) (500 mg) in methylene chloride (10 ml ), triethylamine (677 µl) and benzenesulfonyl chloride (229 µl) were added. The reaction mixture was stirred at room temperature for 4 h, water was added, the phases were separated and the inorganic was extracted with ethyl acetate (x3). The organic layers were pooled, washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane / ethyl acetate 3: 1) yielded trans1-benzenesulfonyl-3- (3-chlorophenyl) -4-phenyl-piperidine (0.66 g, 98%) as a foam white, MS: 411 (M, 1 Cl).

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Step 2: to a solution of trans-1-benzenesulfonyl-3- (3-chlorophenyl) -4-phenyl-piperidine (150 mg) and boronic acid (3-methylsulfonylphenyl) (109 mg) in a mixture of DMA / water ( 2.1 ml, 20: 1) potassium fluoride (42.3 mg), tetracis (triphenylphosphine) palladium (0) (50.5 mg) and triphenylphosphine (22.9 mg) were added. The reaction mixture was irradiated with microwave at 160 ° C at intervals of up to 80 min. Water was added, the phases were separated and the inorganic was extracted with diethyl ether (x2). The organic layers were pooled, washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane / ethyl acetate 1: 1) yielded trans-1benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine (51 mg, 26%) in the form of a white foam, MS: 531.5 (M + H) +.

Example 37

trans- [3 '- (1-Benzenesulfonyl-4-phenyl-piperidin-3-yl) -biphenyl-3-yl] -methylamine

Step 1: analogously to Example 36, from trans-1-benzenesulfonyl-3- (3-chlorophenyl) -4-phenylpiperidine and 3 (N-Boc) -aminomethylphenylboronic acid tert-butyl ester of trans- [ 3 '- (1-Benzenesulfonyl-4-phenylpiperidin-3-yl) biphenyl-3-ylmethyl] -carbamine as a colorless oil, MS: 483.3 (M-C4H9) +.

Step 2: Trans- [3 '- (1-Benzenesulfonyl-4-phenyl-piperidin-3-yl) -biphenyl-3-ylmethyl] -carbamic acid (10 mg) was treated in ethanol (0 , 2 ml) with a saturated solution of HCl in ethanol (0.2 ml) for 4 h at room temperature. The solution was evaporated and redissolved in an aqueous solution of NaHCO3 and ethyl acetate. The phases were separated and the inorganic was extracted with ethyl acetate (x2). The pooled organic layers were washed with hypersaline solution, dried (Na2SO4) and concentrated. Column chromatography (Isolute Flash NH2, n-heptane / ethyl acetate, 1: 3) yielded trans- [3 '- (1-benzenesulfonyl-4-phenylpiperidin-3-yl) -biphenyl-3-yl] -methylamine (7 mg) in the form of a colorless oil, MS: 483.5 (M + H) +.

Example 38

trans-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Step 1: at 0 ° C to a solution of rac-trans-3- (m-chlorophenyl) -4-phenylpiperidine (CAS reg. No. [134823-41-9]) in THF (15 ml) di- dicarbonate was added tert-butyl (481.8 mg) and 4-dimethylaminopyridine (22.5 mg). The reaction mixture was stirred at RT for 2.5 hours. Additional di-tert-butyl dicarbonate (200 mg) was added and stirring was continued overnight. A saturated aqueous solution of NaHCO3 was added, the phases were separated and the inorganic was extracted with ethyl acetate (x2). The pooled organic layers were washed with hypersaline solution, dried (Na2SO4) and concentrated. Column chromatography (Isolute Flash NH2, n-heptane / ethyl acetate, 3: 1) yielded tert-butyl ester of trans-3- (3-chlorophenyl) -4-phenyl-piperidine-1-carboxylic acid (602 mg, 88%) as a colorless oil, MS: 372.0 (M + H, 1Cl) +.

Step 2: to a solution of trans-3- (3-chlorophenyl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and 3- (methylsulfonyl) phenyl) boronic acid (40, 3 mg) in a mixture of DMA / water (1.1 ml, 10: 1) Cs2CO3 (87.6 mg) and [(t-Bu) 2P (OH)] 2PdCl2 (POPd) (8.1 mg) were added. The reaction mixture was irradiated with microwaves at 90 ° C for 10 min and at 140 ° C for 10 and 15 min. Water was added, the phases were separated and the inorganic was extracted with ethyl acetate (x2). The organic layers were pooled, washed with hypersaline solution, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane / ethyl acetate 1: 1 and in Isolute Flash NH2, n-heptane / ethyl acetate, 3: 1) yielded trans-3- (3'-methanesulfonyl acid tert-butyl ether) -biphenyl-3-yl) -4-phenyl-piperidine-1 carboxylic acid (33 mg, 49%) in the form of a colorless oil, MS: 509.3 (M + NH4) +.

Example 39

cis-1-Benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine

Step 1: analogously to Example 38, from rac-cis-3- (m-chlorophenyl) -4-phenylpiperidine (CAS reg. # [73525916-2]) and benzenesulfonyl chloride, cis-1-benzenesulfonyl- was prepared 3- (3-Chlorophenyl) -4-phenyl-piperidine in the form of a colorless oil, MS: 412.2 (M + H, 1Cl) +.

Step 2: analogously to Example 38, from cis-1-benzenesulfonyl-3- (3-chlorophenyl) -4-phenylpiperidine and boronic acid (3-methylsulfonylphenyl), cis-1-benzenesulfonyl-3- (3'-methanesulfonyl-) was prepared Biphenyl-3-yl) -4-phenyl-piperidine colorless oil form, MS: 549.3 (M + NH4) +.

Example 40

trans-3- (2 ', 5'-dimethyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

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analogously to Example 38, from tert-butyl ester of trans-3- (3-chlorophenyl) -4-phenylpiperidine-1-carboxylic acid and 2,5-dimethylphenylboronic acid, tert-butyl ester of trans-acid was prepared 3- (2 ', 5'-dimethyl-biphenyl-3-yl) -4-phenylpiperidine-1 carboxylic acid as a colorless oil, MS: 442.3 (M + H) +.

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cis-3- (2 ', 5'-dimethyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Step 1: analogously to Example 38, starting from rac-cis-3- (m-chlorophenyl) -4-phenylpiperidine (CAS reg. # [73525916-2]) and di-tert-butyl dicarbonate, tert- cis-3- (3-chlorophenyl) -4-phenyl-piperidine-1 acid butyl ester

10 carboxylic in the form of a colorless oil, MS: 372.0 (M + H, 1Cl) +.

Step 2: analogously to Example 38, from tert-butyl ester of cis-3- (3-chlorophenyl) -4-phenylpiperidine-1-carboxylic acid and 2,5-dimethylphenylboronic acid, cis-tert-butyl ester was prepared -3- (2 ', 5'-dimethyl-biphenyl-3-yl) -4-phenylpiperidine-1-carboxylic acid as a colorless oil, MS: 442.3 (M + H) +.

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Example 42

cis-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Similarly to Example 38, from tert-butyl ester of cis-3- (3-chlorophenyl) -4-phenylpiperidine-1-carboxylic acid and 3- (methylsulfonyl) phenylboronic acid, tert-butyl ester of acid was prepared cis-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenylpiperidine-1-carboxylic acid as a colorless oil, MS: 509.2 (M + NH4) +.

Example 43

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trans-3- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Similarly to Example 38, from tert-butyl ester of trans-3- (3-chlorophenyl) -4-phenylpiperidine-1-carboxylic acid and 5- (methylsulfonyl) -3-pyridinboronic acid, tert-butyl ester was prepared of trans-3- [3- (5-methanesulfonyl-pyridin-3-yl) acid

Phenyl] -4-phenyl-piperidine-1-carboxylic acid in the form of a colorless oil, MS: 493.2 (M + H) +.

Example 44

trans-3- (3'-methyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Similarly to Example 38, from tert-butyl ester of trans-3- (3-chlorophenyl) -4-phenylpiperidine-1-carboxylic acid and m-tolylboronic acid, tert-butyl ester of trans-3 acid was prepared - (3'-methyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid in the form of a colorless oil, MS: 428.4 (M + H) +.

40 Example 45

cis-5- (3'-methanesulfonyl-biphenyl-3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Step 1: analogously to Example 38, step 1, from cis-5- (3-chlorophenyl) -4-phenylpiperidin-2-one (prepared

45 analogously to W. Barr, J.W. Cook, J. Chem. Soc. 438, 1945) and di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine in dichloromethane, cis-5- (3-chlorophenyl) -2-oxo-4 acid tert-butyl ester was prepared -phenylpiperidine-1 carboxylic acid in the form of a pale yellow oil, MS: 386.2 (M + H, 1Cl) +.

Step 2: analogously to Example 38, from cis-5- (3-chlorophenyl) -2-oxo-4-phenylpiperidine-1 tert-butyl ester

Carboxylic and 3- (methylsulfonyl) phenylboronic acid was prepared cis-5- (3'-methanesulfonyl-biphenyl-3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester colorless oil, MS: 406.5 (M + H, -BOC) +.

Example 46

Cis-5- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Similarly to Example 38, from tert-butyl ester of cis-5- (3-chlorophenyl) -2-oxo-4-phenylpiperidine-1-carboxylic acid and 5- (methylsulfonyl) -3-pyridinboronic acid, tert-butyl was prepared cis-5- [3- (5-methanesulfonylpyridine-3-yl) -phenyl] -2-oxo-4-phenyl-piperidine-1-carboxylic acid ester as a white solid, MS: 507.1 ( M + H) +.

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cis-5- (2 ', 5'-dimethyl-biphenyl-3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester

Similarly to Example 38, from cis-5- (3-chlorophenyl) -2-oxo-4-phenylpiperidine-1 acid tert-butyl ester

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carboxylic and 2,5-dimethylphenylboronic acid, cis-5- (2 ', 5'-dimethyl-biphenyl-3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester was prepared of colorless oil, MS: 456.4 (M + H) +.

Example 48

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3- (3'-Methanesulfonyl-biphenyl-3-yl) -4-o-tolyl-piperazin-1-carboxylic acid tert-butyl ester

Step 1: analogously to Example 33, step 2, 2-Bromo-N-o-tolyl-acetamide was prepared from o-toluidine and bromoacetyl bromide as a crude product, which was directly subjected to the following reaction.

Step 2: analogously to Example 33, step 3, from 2-amino-1- (3-bromophenyl) -ethanol (Example 33, step 1) and 2-bromo-Non-tolyl-acetamide, 2- [2- (3-Bromophenyl) -2-hydroxy-ethylamino] -No-tolyl-acetamide as an off-white solid, MS: 363.2 (M + H, 1Br) +.

Step 3: to 2- [2- (3-bromophenyl) -2-hydroxy-ethylaminol-No-tolyl-acetamide (4 g) in THF (100 ml) DMAP (134 mg) and (BOC) 2O ( 2.89 g) in THF (100 ml) at 0 ° C. The mixture was stirred at room temperature for 2 h. An aqueous solution of NaHCO3 and ethyl acetate was added, the phases were separated and the inorganic was extracted with ethyl acetate (x2). The pooled organic layers were washed with hypersaline solution, dried (Na2SO4) and concentrated. Column chromatography (SiO2, n-heptane / ethyl acetate, 1: 1) yielded acid tert-butyl ester [2

20 (3-bromophenyl) -2-hydroxyethyl] - (o-tolyl-carbamoyl-methyl) -carbamic (0.88 g, 88%) as a colorless oil, MS: 463.1 (M + H, 1Br) +.

Step 4: analogously to Example 33, step 5, from tert-butyl ester of [2- (3-bromophenyl) -2-hydroxyethyl] - (otolylcarbamoyl-methyl) -carbamic acid, tert-butyl ester of 3- (3-Bromophenyl) -5-oxo-4-o-tolyl-piperazin-1 acid

25 carboxylic in the form of a pale orange foam, MS: 445.1 (M + H, 1Br) +.

Step 5: analogously to Example 34, from tert-butyl ester of 3- (3-bromophenyl) -5-oxo-4-o-tolyl-piperazine-1-carboxylic acid 3- tert-butyl ester of 3- acid was prepared (3-Bromophenyl) -4-o-tolyl-piperazin-1-carboxylic in the form of a white foam, MS: 431.2 (M + H, 1Br) +.

Step 6: Analogously to Example 33, from tert-butyl ester of 3- (3-bromophenyl) -4-o-tolyl-piperazine-1-carboxylic acid and (3-methylsulfonylphenyl) boronic acid, tert-butyl- 3- (3'-Methanesulfonyl-biphenyl-3-yl) -4o-tolyl-piperazin-1-carboxylic acid ester in the form of a white foam, MS: 507.1 (M + H) +.

35 Example 49

3- [3- (5-Methanesulfonyl-pyridin-3-yl) -phenyl] -4-o-tolyl-piperazin-1-carboxylic acid tert-butyl ester

Analogously to Example 33, step 6, from 3- (3-bromophenyl) -4-o-tolyl-piperazin-1 tert-butyl ester

Carboxylic acid and 5- (methylsulfonyl) -3-pyridinboronic acid 3- [3- (5-methanesulfonylbiphenyl-3-yl) -phenyl] -4-o-tolyl-piperazin-1- tert-butyl ester was prepared carboxylic in the form of an orange oil, MS: 508.1 (M + H) +.

Example 50

45 4-Benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-o-tolyl-piperazine

Step 1: 3- (3'-Methanesulfonyl-biphenyl-3-yl) -4-o-tolyl-piperazine-1-carboxylic acid tert-butyl ester (90 mg) in ethanol (1 ml) was treated with a saturated solution of HCl in ethanol (1 ml) at room temperature overnight. The solution was concentrated in vacuo, yielding crude 2- (3'-methanesulfonyl-biphenyl-3-yl) -1-o-tolyl-piperazine hydrochloride,

50 MS: 407.3 (M + H) +.

Step 2: To a solution of 2- (3'-methanesulfonyl-biphenyl-3-yl) -1-o-tolyl-piperazine hydrochloride (58 mg) in THF (1 ml) was added sodium hydride (12.3 mg , 60% in mineral oil). After stirring for 30 min at room temperature, benzenesulfonyl chloride was added at 0 ° C and stirring was continued at room temperature overnight. Be

Water and ethyl acetate were added, the phases were separated and the inorganic was extracted with ethyl acetate (x3). The pooled organic layers were washed with water and hypersaline solution, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane / ethyl acetate 2: 1) yielded 4-benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl3-yl) -1-o-tolyl-piperazine (55 mg, 42%) in the form of colorless oil, MS: 547.1 (M + H) +.

60 Example A

Film-coated tablets containing the following ingredients can be manufactured in a conventional manner:

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Ingredients For each tablet Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Hydrated lactose 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium glycolate of starch 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Core weight) 120.0 mg 350.0 mg

Coating Film:

Hydroxypropyl methylcellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1 , 6 mg

The active ingredient was screened and mixed with microcrystalline cellulose, and the mixture was granulated with a solution of polyvinylpyrrolidone in water. The granulate was mixed with sodium starch glycolate and magnesium stearate and compressed, yielding cores of 120 or 350 mg, respectively. The cores were washed with an aqueous solution / suspension of the coating film indicated above.

Example B

Capsules containing the following ingredients can be manufactured in a conventional manner:

Ingredients For each capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Corn starch 20.0 mg Talc 5.0 mg

The components were screened and mixed and used to fill size 2 capsules.

Example C

Solutions for injection may have the following composition:

Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid c.s. for pH 5.0 Water solutions for injection up to 1.0 ml

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0 ml by adding the residual amount of water. The solution was filtered, used to fill vials using an appropriate excess and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:

Compound of formula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated soybean oil 8.0 mg Partially hydrogenated vegetable oils 34.0 mg Soybean oil 110.0 mg Capsule content weight 165.0 mg

Gelatin capsule

Gelatin 75.0 mg Glycerol (85%) 32.0 mg Karion 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Yellow iron oxide 1.1 mg

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The active ingredient was dissolved in a hot molten mixture of the other ingredients and the resulting mixture was used to fill soft gelatin capsules of the appropriate size. The filled soft gelatin capsules were treated following the usual procedures.

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Example E

Envelopes containing the following ingredients can be manufactured in a conventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powders 1,015.0 mg Microcrystalline cellulose (Avicel PH 102) 1,400.0 mg Sodium carboxymethylcellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mg Magnesium stearate 10.0 mg Additives flavorings 1.0 mg

The active ingredient was mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose, and the mixture was granulated with a mixture of polyvinylpyrrolidone in water. The granulate was mixed with magnesium stearate and flavoring additives and used to fill envelopes.

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Claims (21)

E09761672 02-09-2014 1. Compounds of formula (I): image 1 5 wherein: A is -C (O) -, -CH2-C (O) -, -C (O) -CH2-or -CH2-CH2-, D is N or CH, E is arylene that can be optionally substituted with 1 to 4 substituents selected 10 independently of the group consisting of halogen, lower alkyl and fluoro-lower alkyl, R1 is lower alkyl-OC (O) or R4-SO2, R2 is lower alkyl or aryl, in which the aryl may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower fluoroalkyl and lower fluoroalkoxy, R3 is aryl or heteroaryl, wherein aryl or heteroaryl may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower fluoroalkyl, lower fluoroalkoxy, COOH, lower alkyl-SO2 , lower alkyl-SO2-NH, lower alkyl-SO2-N (lower alkyl), COOH-lower alkyl, lower hydroxyalkyl, NH2 lower alkyl, N (H, lower alkyl)-lower alkyl, N (lower alkyl) 2-lower alkyl , NO2, CN, NH2-SO2, 20 N (H, lower alkyl) -SO2, N (lower alkyl) 2-SO2, lower alkyl-NH-SO2 and lower alkyl-N (lower alkyl) -SO2, R4 is lower alkyl, aryl or heteroaryl, in which aryl or heteroaryl may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, fluoro-lower alkyl and fluoro-lower alkoxy, 25 and pharmaceutically acceptable salts and esters thereof, in which the term "lower" refers to a group consisting of one to seven carbon atoms. 2. Compounds according to claim 1, wherein A is -C (O) -, -CH2-CH2-or -C (O) -CH2-. 3. Compounds according to any of claims 1 to 2, wherein D is N.

Four.

Compounds according to any one of claims 1 to 2, wherein D is CH.

5.

Compounds according to any one of claims 1 to 4, wherein E is phenylene.

35

6.

Compounds according to any one of claims 1 to 5, wherein E is 1,3-phenylene.

7.

Compounds according to any one of claims 1 to 6, wherein R1 is lower alkyl-O-C (O).

Compounds according to any one of claims 1 to 7, wherein R1 is (CH3) 3C-O-C (O). 9. Compounds according to any of claims 1 to 6, wherein R1 is R4-SO2 and R4 is as defined in claim 1. Compounds according to any one of claims 1 to 9, wherein R2 is lower alkyl or phenyl, wherein the phenyl may optionally be substituted with 1 to 2 substituents independently selected from the lower alkyls. 11. Compounds according to any of claims 1 to 10, wherein R2 is isopropyl, phenyl or 250 methylphenyl. 12. Compounds according to any of claims 1 to 11, wherein R3 is phenyl or pyridinyl, wherein phenyl or pyridinyl may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, lower alkyl, alkoxy lower, COOH, lower alkyl-SO2, lower alkyl SO2-NH, COOH-lower alkyl, lower hydroxyalkyl, NH2-lower alkyl, NO2, CN, NH2-SO2 and N (H, lower alkyl) -SO2.  -27 E09761672 02-09-2014 5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 60

13.

Compounds according to any one of claims 1 to 12, wherein R3 is phenyl or pyridinyl, wherein phenyl or pyridinyl may optionally be substituted with 1 to 2 substituents independently selected from the group consisting of lower alkyl-SO2, lower hydroxyalkyl, NH2-lower alkyl and NH2-SO2.

14.

Compounds according to any one of claims 1 to 13, wherein R 3 is 3-methanesulfonylphenyl, 4-hydroxymethyl-3-methanesulfonylphenyl, 3-sulfamoylphenyl, 5-methanesulfonyl-pyridine-3-yl or 3-aminomethylphenyl.

fifteen.

Compounds according to any one of claims 1 to 14, wherein R 4 is lower alkyl, phenyl or isoxazolyl, wherein the phenyl or isoxazolyl may optionally be substituted with 1 to 2 substituents independently selected from the group consisting of halogen and alkyl lower.

16.

Compounds according to any one of claims 1 to 15, wherein R 4 is lower alkyl or phenyl, wherein the phenyl can be optionally substituted with halogen.

17.

Compounds according to any one of claims 1 to 16, wherein R 4 is ethyl, isopropyl, phenyl or 2-fluorophenyl.

18.

Compounds according to any of claims 1 to 17, selected from the group consisting

from: 4 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4-carboxylic acid, 4' - (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidine -4-yl) -biphenyl-3-carboxylic, 1-benzenesulfonyl-4- (2 ', 5'-dimethyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-4-yl) -3-phenyl-imidazolidin-2-one, 3 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-4 -carboxylic acid, 3 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-carboxylic acid, 1-benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl ) -3-phenyl-imidazolidin-2-one, N- [3 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide, N- [ 4 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-3-yl] -methanesulfonamide, 3- [3' - (1-benzenesulfonyl-2-oxo-3- acid phenyl-imidazolidin-4-yl) -biphenyl-4-yl] -propionic acid, 3 '- (1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl) -biphenyl-2-carboxylic acid, (RS ) -1-benzenesulf onyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1- (propane -2-sulfonyl) -imidazolidin-2-one, 1 - ((2-fluoro-benzenesulfonyl) -3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 3- isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1- (5-methyl-isoxazol-4-sulfonyl) -imidazolidin-2-one, 1-benzenesulfonyl-4- (4'-hydroxymethyl-3 '-methanesulfonyl-biphenyl-3-yl) -3-phenyl-imidazolidin-2-one, 3-isopropyl-1-methanesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 1-ethanesulfonyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 1-benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-4- il) -3-phenyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 1-benzenesulfonyl -3-isopropyl-4- (3'-nitro-biphenyl-3-yl) -imidazolidin-2-one, 1-benzenesulfonyl-4- (5'-fluoro-2'-methyl-biphenyl-3-yl) - 3-isopropi l-imidazolidin-2-one, 1-benzenesulfonyl-3-isopropyl-4- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -imidazolidin-2-one, 3 '- (1 -benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic, 1-benzenesulfonyl-4- (2'-chloro-5'-fluoro-biphenyl-3-yl) -3- isopropyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (5'-chloro-2'-methyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (5 '-fluoro-2'-methoxy-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 3' - (1-benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -6 3 '- (1-Benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic acid, 1-benzenesulfonyl-4- (3-chloro-biphenyl-3-carbonitrile 5'-ethoxy-2'-fluoro-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (2 ', 5'-dimethyl-biphenyl-3-yl) -3 -isopropyl-imidazolidin-2-one, 1-benzenesulfonyl-4- (2 ', 5'-difluoro-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 4-benzenesulfonyl-6- (3' -methanesulfonyl -biphenyl-3-yl) -1-phenyl-piperazin-2-one, 4-benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazine, C- [3 '- ( 4-benzenesulfonyl-1-phenyl-piperazin-2-yl) -biphenyl-3-yl] -methylamine, trans-1-benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine , trans- [3 '(1-Benzenesulfonyl-4-phenyl-piperidin-3-yl) -biphenyl-3-yl] -methylamine, trans-3- (3'-methanesulfonyl-biphenyl-) acid tert-butyl ester 3-yl) -4-phenyl-piperidin-1-carboxylic acid, cis-1-Benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine, tert-butyl ester of trans acid -3- (2 ', 5'-dimethyl-biphenyl-3-yl) -4-phenyl-piperidin-1-carboxylic acid, cis-3- (2', 5'-dimethyl-biphenyl acid tert-butyl ester) -3-yl) -4-phenyl-piperidin-1-carboxylic acid, cis-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester trans-3- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, trans-3 acid tert-butyl ester - (3’-methyl-biphenyl-3-yl) -4-phenyl-piperidine-1-carboxylic acid, -28 E09761672 02-09-2014 cis-5- (3'-methanesulfonyl-biphenyl-3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester, cis-5- [tert-butyl ester] 3- (5-Methanesulfonyl-pyridin-3-yl) -phenyl] -2-oxo-4-phenyl-piperidin-1-carboxylic acid, cis-5- (2 ', 5'-dimethyl acid tert-butyl ester) -biphenyl-3-yl) -2-oxo-4-phenyl-piperidin-1-carboxylic acid, tert-butyl ester of 3- ((3'-methanesulfonyl-biphenyl-3-yl) -4-o-tolyl -piperazine-1-carboxylic acid, 5-tert-Butyl ester of 3- [3- (5-methanesulfonyl-pyridin-3-yl) -phenyl] -4-o-tolyl-piperazine-1-carboxylic acid and 4-benzenesulfonyl-2- (3'- methanesulfonyl-biphenyl-3-yl) -1-o-tolyl-piperazine, and pharmaceutically acceptable salts and esters thereof. 19. Compounds according to any of claims 1 to 18, selected from the group consisting 10 of: 1-benzenesulfonyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -3-phenyl-imidazolidin-2-one, 3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -1- (propane-2-sulfonyl) -imidazolidin-2-one, 1 - ((2-fluoro-benzenesulfonyl) -3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidine-2 -one 1-ethanesulfonyl-3-isopropyl-4- (3'-methanesulfonyl-biphenyl-3-yl) -imidazolidin-2-one, 1-Benzenesulfonyl-4- (4'-hydroxymethyl-3'-methanesulfonyl-biphenyl-3-yl) -3-isopropyl-imidazolidin-2-one, 1-benzenesulfonyl-3-isopropyl-4- [3- (5 -methanesulfonyl-pyridin-3-yl) -phenyl] -imidazolidin-2-one, 3 '- (1-benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl) -biphenyl-3-sulfonic acid amide , 4-benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-phenyl-piperazine, trans-1-benzenesulfonyl-3- (3'-methanesulfonyl-biphenyl-3-yl) -4-phenyl -piperidine, 20- [3 '(1-Benzenesulfonyl-4-phenyl-piperidin-3-yl) -biphenyl-3-yl] -methylamine, cis-5- (3'-methanesulfonyl-biphenyl-) acid tert-butyl ester 3-yl) -2-oxo-4-phenyl-piperidine-1-carboxylic acid, tert-butyl ester of 3- ((3'-methanesulfonyl-biphenyl-3-yl) -4-o-tolyl-piperazine- 1-carboxylic and 4-benzenesulfonyl-2- (3'-methanesulfonyl-biphenyl-3-yl) -1-o-tolyl-piperazine, and pharmaceutically acceptable salts and esters thereof. 25 20. Process for the preparation of compounds of formula (I) according to any of claims 1 to 19, the process comprising reacting a compound of formula (II): image2 with a compound of formula R1-Cl, wherein R1, R2, R3, A, D and E are as defined in any one of claims 1 to 19. 21. Pharmaceutical compositions comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier and / or adjuvant. 22. Compounds according to any of claims 1 to 19, for use as therapeutic active substances. 23. Compounds according to any of claims 1 to 19, for use as active substances Therapeutics for the treatment and / or prophylaxis of diseases that are modulated by agonists of LXR-alpha 40 and / or LXR-beta.

24.

Use of compounds according to any one of claims 1 to 19, for the preparation of medicaments for the therapeutic and / or prophylactic treatment of diseases that are modulated by LXR-alpha and / or LXR-beta agonists.

25.

Use of compounds according to any one of claims 1 to 19 for the preparation of medicaments for the therapeutic and / or prophylactic treatment of increased lipid levels, increased cholesterol levels, low HDL cholesterol level, high LDL cholesterol level, diseases atherosclerosis, diabetes, non-insulin-dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis,

Four. Five 50 inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, liver cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, impaired / improved cognitive function, HIV, cancer, age-related forms of macular degeneration, forms Inherited from macular degeneration and / or Stargadt disease.  55 *** -29